Untersuchungen zur Biotransformation neuer substituierter Piperidylbenzilate
The suitability of basic substituted benzilic esters with partially available dualistic anticholinergic and dopaminergic properties is examined and discussed for the treatment of Parkinson disease recently. The knowledge of the biotransformation is important for the evaluation of these substances. Purpose of the present thesis was the investigation of the metabolism of some selected benzilates in rats. Therefore four different derivatives were chosen: (R,S)-N-Methyl-4-piperidyl 3,4-dimethoxybenzilate (1), (R,S)-N-Methyl-3-piperidyl 3,4-dimethoxybenzilate (2), N-Methyl-4-piperidyl 3,3'-dimethoxybenzilate (3), (R,S)-N-Methyl-3-piperidyl 3,3'-dimethoxybenzilate (4). After purification of urine and faeces, the characterization of the metabolites was determined by TLC, HPLC and UV. MS, also coupled with GC, represented the most important method for identification. The evidence for aromatic oxygenation in p-position was succeeded by NMR-spectroscopy. Several metabolic processes appeared: ester cleavage, aromatic C-oxygenation, O-dealkylation, N-dealkylation, formation of lactam, N-oxidation, oxidation to benzophenone and the methylation and glucuronidation/sulphatation of phenolic derivatives. All these multiple reactions were observed at single benzilates for the first time. C-Oxygenation represented the main decomposition way for the 3,4-dimethoxy esters and, additionally, ester cleavage for 2. O-Dealkylation and ester cleavage were the important reactions of metabolism of the 3,3'-dimethoxy derivatives. The formation of lactams as metabolites could be verified by comparison to synthesized reference substances. In comparison to the metabolic pathways, the results of the biomimetic examinations of 1, 2 and 3 show agreement in the formation of benzilic acids (ester cleavage), N-oxides, N-dealkylated esters and benzophenones. But this chemical method can't be used as modell for C-oxygenation, O-dealkylation and lactamisation.
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School:Humboldt-Universität zu Berlin
Source Type:Master's Thesis
benzilic acid derivatives
Date of Publication:05/31/2002